PROJECT SUMMARY/ ABSTRACT Diabetes mellitus is a chronic progressive disease that afflicts almost 30 million Americans and 90-95% of these individuals have type 2 diabetes (T2DM). Poor T2DM self-care is a major cause of high morbidity and mortality, as excellent self-care improves glycemic control, prevents or delays the T2DM progression, and reduces premature mortality. T2DM self-care regimen is complex and challenging, and requires intact cognitive abilities and mood function. However, cognitive and mood dysfunctions are common in T2DM patients and are associated with worse T2DM self-care behaviors. Cognitive abilities are linked to specific brain areas (pre-frontal cortices; hippocampus), and relationships between T2DM self-care, brain structure, cognition and/or mood status have not been reported. Furthermore, the long-term impact/role of glucose control status (as measured by hemoglobin A1C [A1C]) on these relationships is unknown. Using non-invasive brain magnetic resonance imaging (MRI) procedures, preliminary studies found significant brain changes in cognitive and mood control sites that influence T2DM self-care abilities (pre-frontal cortices [executive thinking], hippocampus [memory and mood]) and linked these alterations to T2DM self-care in a small sample of subjects (n=9). Findings also indicated significant brain changes with altered A1C levels. However, the small number of T2DM subjects restricted our ability to control for important covariates, such as age, gender, A1C, and body mass index. Using a two-group comparative design, we will examine brain integrity in cognitive and mood control areas (MRI/diffusion tensor imaging), T2DM self-care (Summary of Diabetes Self-Care Activities scale), and cognitive (Montreal Cognitive Assessment questionnaire) and mood functions (Beck Depression and Beck Anxiety questionnaires) in 60 T2DM and 60 healthy controls. Specific aims are to: 1) compare brain structures (pre- frontal cortices and hippocampus), mood, and cognition scores between T2DM and age- and gender-matched non-DM healthy control subjects, as well as between genders in T2DM and controls; 2) evaluate the relationships between brain changes and self-care management and mood and cognitive scores in T2DM subjects; 3) determine associations of A1C levels on brain changes in T2DM subjects; and 4) examine brain changes over time (longitudinal study for brain plasticity or tissue injury progression). In summary, T2DM outcomes are dependent upon self-care abilities which can be impacted by cognition and mood, but the relationships between T2DM self-care, cognition, mood, and brain changes remain unclear. The proposed study will examine brain changes between T2DM and healthy subjects, as well as gender differences, and investigate relationships between brain changes and self-care, mood, cognition, and impact of A1C levels in T2DM subjects. Information from this study could impact clinical practice through the identification and testing of novel therapeutic interventions to protect or restore the brain, minimize or prevent cognitive and mood dysfunction, and thus, improve T2DM self-care and health outcomes in this high-risk patient population.